Sorbefacients and preparations for percutaneous absorption containing the same

ABSTRACT

Percutaneous sorbefacients comprising hexylene glycol and 1-menthol, more particularly, percutaneous sorbefacients for female hormones or derivatives thereof; and preparations for percutaneous absorption which comprise a styrene/isoprene/styrene block copolymer and/or polyisobutylene, a softener and a tackifier as the base components, hormones, in particular, follicle hormone and/or luteal hormone as the drug component and hexylene glycol and 1-menthol as a sorbefacient.

TECHNICAL FIELD

The present invention relates to the field of a percutaneous drugtherapy and relates to a preparation for percutaneous absorptioncontaining hexylene glycol and 1-menthol as sorbefacients. Moreparticularly, it relates to a preparation for percutaneous absorptionwhich is characterized in using a styrene-isoprene-styrene blockcopolymer, a softener and a tackifier as a base component and hexyleneglycol and 1-menthol as sorbefacients whereby permeation of apharmaceutical agent through skin is made better and a predeterminedamount of a pharmaceutical agent can be precisely and surely applied toa patient.

BACKGROUND ART

Estradiol contained in follicular hormones is secreted from ovary whenfemales are in a reproducible period. Therefore, females around thestage of perimenopause are deficient mostly in estradiol and suffer fromclimacteric changes and menopausal disorder. In order to improve thosesymptoms, a therapy by orally administering agents is carried out atpresent but, since they are quickly metabolized and inactivated bydigestive organs such as stomach and intestine, liver, etc., it isnecessary to take high doses of estradiol for expecting a sufficientexpression of the pharmaceutical effect. In addition, there is a risk ofan increase in expression of adverse actions and the like due to thehigh doses.

Under such circumstances, there has been attempts where a therapy iscarried out in which estradiol is made to reach the blood by making itsmetabolism little by means of a percutaneous administration. On theother hand, there have been other attempts where anotherhormone—luteinizing hormone—is absorbed percutaneously whereby theadverse action in the administration of estradiol is suppressed. InJapanese Patent Laid-Open No. 342532/1992, there is proposed apercutaneously absorbing preparation mainly comprising estradiol andluteinizing hormone as pharmaceutical ingredients and an acrylateadhesive consisting of 2-ethylhexyl acrylate and N-vinyl-2-pyrrolidoneas an adhesive. However, an acrylate adhesive has a low releasingability of pharmaceuticals and has a strong irritation to skin and,therefore, it is hardly durable for a continuous administration during along period.

In Japanese Patent Laid-Open No. 51623/1994, there is proposed a methodwhere the pharmaceutical ingredients—estradiol and norethisteroneacetate—are dissolved in a gel comprising hydroxypropyl cellulose andethanol to make them into a reservoir type and release of thepharmaceutical ingredients is controlled using a permeability adjustingmembrane. However, ethanol has a strong irritation to skin and there isa problem such as an adverse action causing a flare at the applied areain a high frequency. On the other hand, a percutaneous patch comprisinga styrene-isoprene-styrene block copolymer using crotamiton as asolubilizer is proposed in International Patent Laid-Open WO 91/17752and Japanese Patent Laid-Open No. 148145/1993. However, there is aproblem in its stability that, when crotamiton is used as a solubilizer,the styrene-isoprene-styrene block copolymer itself is dissolved incrotamiton whereby the expected cohesive force is not achieved.

Hexylene glycol (generic name; its chemical name is2-methyl-2,4-pentanediol) is usually used as moisturizer, solvent,cleaning agent in industry, hydraulic fluid, softener/softening agentfor leather fiber, etc., agent for ink, agent for photography and thelike. In Japanese Patent Laid-Open Nos. 109220/1995 and 53338/1996,there are proposed the agents for external use where hexylene glycol isused as an antibacterial agent. In International Patent Laid-Open WO96/19976 and Japanese Patent Laid-Open No. 138153/1995, there areproposed the agents for external use where hexylene glycol is used as asorbefacient. However, hexylene glycol has a high compatibility withacrylate bases and, in achieving a sufficient sorbefacient effect, it isnecessary to compound hexylene glycol in a large amount. There is anadditional problem of lowering of adhesive property and influence on thebasic physical property of the preparation caused by compounding of alarge quantity of hexylene glycol.

In view of the above problems, the present inventors have carried out anintensive investigation with an object of providing a percutaneouspreparation or base in which

1) a high cutaneous permeation of pharmaceutical ingredients and

2) stabilization of physical property of the base are attempted and, asa result, the present invention has been accomplished.

DISCLOSURE OF THE INVENTION

As a result of an intensive investigation for solving theabove-mentioned problems, the present inventors have found that acombination of hexylene glycol (chemical name: 2-methyl-2,4-pentanediol)and 1-menthol has a high percutaneous sorbefacient action. Moreparticularly, they have found that hexylene glycol and 1-menthol have anexcellent percutaneously sorbefacient action to female hormones andderivatives thereof such as follicular hormone, luteinizing hormone andderivatives thereof. Thus, the present invention relates to asorbefacient comprising hexylene glycol and 1-menthol or, preferably, toa percutaneously sorbefacient for female hormones or derivativesthereof.

The present invention further relates to a percutaneous base containinga base component for percutaneous absorption and hexylene glycol and1-menthol having sufficient amounts for achieving a percutaneouslysorbefacient action. With regard to the base component for percutaneousabsorption, that which contains a styrene-isoprene-styrene blockcopolymer and/or polyisobutylene, softener and tackifier is preferred.

To be more particularly, it has been found that a percutaneouslyabsorbing preparation having good cohesive property, stabilized physicalproperty of the preparation and good skin permeation of thepharmaceutical agent can be prepared by the use of astyrene-isoprene-styrene block copolymer and/or polyisobutylene,softener, tackifier, hexylene glycol and 1-menthol as a base componentwhereupon the present invention has been achieved.

The present invention relates to a base for a percutaneously absorbingpatch containing a styrene-isoprene-styrene block copolymer and/orpolyisobutylene, softener, tackifier, hexylene glycol and 1-menthol as abase component and also to a percutaneously absorbing patch containingthe said base for a percutaneously absorbing patch and pharmaceuticals.

BEST MODE FOR CARRYING OUT THE INVENTION

It is necessary that the pharmaceutical agent which is an effectiveingredient of the percutaneously absorbing preparation of the presentinvention is a physiologically active substance and has a percutaneouslyabsorbing ability. Alternatively, the agent may be the so-called prodrugwhich shows a physiological action after being percutaneously absorbed.The agent includes a pharmaceutical acceptable inorganic or organicaddition salt as well.

With regard to the pharmaceutical agent for the percutaneously absorbingpreparation of the present invention, female hormones such as follicularhormone, luteinizing hormone and derivatives thereof are preferablyexemplified. For example, follicular hormone such as estradiol, estrone,estriol, equilin, equilenin and derivatives thereof may listed as anactive ingredient and, preferably, estradiol is mostly used in thepercutaneously absorbing preparation of the present invention. Withregard to the luteinizing hormone, progesterone, hydroxyprogesteronecaproate, hydroxyprogesterone acetate, dydrogesterone, chlormadinoneacetate, ethisterone, dimethisterone, norethisterone, norethisteroneacetate, norethisterone enanthate, ethynodiol acetate, megestrol acetateand allylestrenol are exemplified and, preferably, norethisterone andnorethisterone acetate are mostly used for the percutaneously absorbingpreparation of the present invention.

Besides the above, examples of the pharmaceutical agent which iseffective and able to be used for the percutaneously absorbingpreparation of the present invention are antiemetic agents (such asgranisetron hydrochloride, azasetron hydrochloride, ondansetronhydrochloride and ramosetron hydrochloride), remedies for pollakiuria(such as oxybutynin hydrochloride), calcium antagonists (such asnifedipine, nisoldipine, nicardipine and nitrendipine), corticosteroidsubstances (such as hydrocortisone, prednisolone and clobetasolpropionate), anti-inflammatory/analgesic agents (such as indomethacin,ketoprofen, flurbiprofen, felbinac and ketorolac), hypnotic/sedativeagents (such as phenobarbital, triazolam, nitrazepam and lorazepam),tranquilizers (such as fluphenazine, diazepam and chlorpromazine),antihypertensive agents (such as clonidine, clonidine hydrochloride,pindolol, propranolol, nitrendipine and metoprolol), hypotensivediuretic agents (such as hydrothiazide), antibiotic substances (such aspenicillin, tetracycline, erythromycin and chloramphenicol), anestheticagents (such as lidocaine, dibucaine hydrochloride and ethylaminobenzoate), antibacterial substances (such as benzalkoniumhydrochloride and clotrimazole), vitamins (such as vitamin A),antiepileptic agents (such as nitrazepam), coronary vasodilators (suchas nitroglycerine and isosorbide nitrate), antihistaminic agents (suchas diphenhydramine and chlorpheniramine), antitussive agents (such astulobuterol hydrochloride, salbutamol, ketotifen fumarate, tranilast andisoproterenol hydrochloride), antidepressants (such as clomipraminehydrochloride and amitriptyline hydrochloride), cerebral circulationimproving agents (such as dihydroergotoxine mesylate and ifenprodil),anti-tumor agents (such as 5-fluorouracil), muscle relaxants (such aseperisone and dantrolene), analgesics (such as fentanyl and morphine),hormone preparations of a polypeptide type (luteinizinghormone-releasing hormone [LH-RH] and thyrotropin-releasing hormone[TRH]), peripheral blood vessel dilators, immunomodulators (such aspolysaccharides, auranofin and lobenzarit), cholagogues (such asursodeoxycholic acid), diuretics (such as hydroflumethiazide), agentsfor diabetes mellitus (such as tolbutamide), remedies for gout (such ascolchicine), anti-parkinsonian agents (such as amantadine and levodopa)and anti-dizziness agents (such as difenidol and betahistine) and,although the compounding amount thereof effective for the therapy isdifferent for the object of compounding, it is usually preferred to be0.1–10% by weight to the preparation. When those pharmaceuticals do notcause inconvenience by their interaction, two or more of them may bejointly used upon necessity.

According to the combination of a styrene-isoprene-styrene blockcopolymer and/or polyisobutylene, softener, tackifier, hexylene glycoland 1-menthol in the percutaneously absorbing base of the presentinvention, a high release of pharmaceuticals which has not been achievedby the conventional single acrylate base is now possible and, inaddition, a high permeation through the skin is available.

Further, hexylene glycol can be used within such a range that the basecomponent, particularly a styrene-isoprene-styrene block copolymerand/or polyisobutylene, is not substantially dissolved therein or itssubstantial dissolving therein is not observed while 1-menthol can bealso used within such a range that it does not affect a physicalproperty and, accordingly, good tackiness and stability can be achieved.

Contents of those essential components in the total amount of thepreparation are as follows.

Thus, 10–40% by weight, preferably 15–30% by weight or, more preferably,17–23% by weight for a styrene-isoprene-styrene block copolymer; 2–10%by weight, preferably 2.5–7% by weight or, more preferably, 3–5% byweight for polyisobutylene; 10–60% by weight, preferably 12–55% byweight or, more preferably, 15–50% by weight for a softener; 20–60% byweight, preferably 23–57% by weight or, more preferably, 25–50% byweight of a tackifier; and a combination within such a range affords thebest advantage of the present invention.

When the amount of the styrene-isoprene-styrene block copolymer and/orpolyisobutylene is less than the above range, a cohesive force isinsufficient while, when it is more than that, softness of thepreparation is little resulting in a problem in terms of stickiness.When the amount of the softener is less than the above range, softnessof the preparation is little resulting in a problem in terms ofstickiness while, when it is more than that, softness becomes big butthere is a problem in terms of cohesive force of the preparation. Thetackifier has a compatibility with hexylene glycol and 1-menthol. Whenthe amount of the tackifier is little, a sufficient compounding ofhexylene glycol with 1-menthol is not possible and a sufficientsorbefacient effect by hexylene glycol and 1-menthol is not achieved.

Hexylene glycol which is one of the components of the present inventionhas been known to be used as a moisturizer and an antibacterial agent asa cosmetic material. However, in the present invention, a sufficientamount thereof is to be compounded as a sorbefacient for thepharmaceutical component and the compounding amount is 1–10% by weight,preferably 1.5–8% by weight or, more preferably, 2–7% by weight. Whenthe compounding amount is less than 1% by weight, stabilizing andsorbefacient effects for the physical property of the base areinsufficient while, when it is more than 10% by weight, a bleeding byhexylene glycol is resulted.

With regard to 1-menthol which is used as a sorbefacient together withhexylene glycol, its sorbefacient effect has been confirmed already butit results in a synergistic effect when combined with hexylene glycol.Its compounding amount is 0.1–7% by weight, preferably 0.5–6% by weightor, more preferably, 1–5% by weight. When the compounding amount is lessthan 0.1% by weight, a sorbefacient effect is insufficient while, whenit is more than 7% by weight, cohesive force of the base componentslowers.

With regard to the compounding ratio of hexylene glycol to 1-menthol,when the ratio in terms of (hexylene glycol):(1-menthol) is 1:0.1 orless, an sorbefacient effect for the pharmaceutical agent is littlewhile, when it is 1:7 or more, hexylene glycol bleeds and cohesive forceof the patch lowers. In the present invention, an advantage is achievedwhen the ratio of hexylene glycol to 1-menthol is within a range of from1:0.1 to 1:7 and, more preferably, when it is from 2:1 to 7:5, thehighest sorbefacient effect is achieved and the physical propertybecomes good as well.

With regard to the dosage form of the percutaneously absorbing patch ofthe present invention, plaster is most preferred and an anhydrousplaster containing substantially no water is particularly preferred.

Examples of the styrene-isoprene-styrene block copolymer arestyrene-isoprene-styrene block copolymers manufactured by Shell Chemical(trade names: Cariflex TR-1107 and Cariflex TR-1111),styrene-isoprene-styrene block copolymers manufactured by NipponSynthetic Rubber (trade names: JSR 5000 and JSR 5100) and astyrene-isoprene-styrene block copolymer manufactured by Nippon Zeon(trade name: Quintac 3421).

Examples of polyisobutylene are polyisobutylene manufactured by Exxon(trade name: Vistanex) and polyisobutylene manufactured by BASF (tradename: Opanol).

Examples of the softener are liquid paraffin, polybutene, castor oil,cotton seed oil, palm oil, coconut oil and process oil.

Examples of the tackifier are alicyclic saturated hydrocarbon resins(such as Arkon P-100 [trade name]), rosin esters (such as KE-311 andKE-100 [trade names] and Super Ester S-100 [trade name]), hydrogenatedalicyclic hydrocarbons (such as Escorez 5300 [trade name]), hydrogenatedresins of a terpene type (such as Clearon P-105 [trade name]),hydrogenated rosin esters (such as Foral 105 [trade name]) and modifiedrosin esters modified with dibasic acid (such as Pentalyn 4741 [tradename]). Those tackifiers may be used by mixing two or more of them uponnecessity.

It is necessary that a film which is to be a support of the presentinvention has a property of, for example, excellent so-called barrierproperty for the prevention of leakage, evaporation and adsorption ofthe pharmaceutical agent. In addition, it preferably has an appropriatesoftness when an apparatus is applied to the skin. With regard to amaterial for the support, there is no particular limitation so far as ithas the above-mentioned conditions and its specific examples arealuminum, ethylene-vinyl acetate copolymer or a saponified productthereof, cellulose acetate, cellulose, Nylon, polyester, polyethylene,polyvinylidene chloride, polycarbonate, polyvinyl alcohol andpolypropylene. Those materials may be made into film, made into alayered film by laminating after making into a form of paper or cloth ifnecessary or subjected to a treatment such as aluminum evaporation orceramic evaporation whereupon a barrier property is improved.

With regard to a film which is to be a detachable liner layer, the filmis necessary to prevent its leakage and evaporation from thepharmaceutical agent layer during the storage of the apparatus and, inaddition, the detachable liner layer should be able to be detached uponthe use of the apparatus. With regard to the material for the detachableliner film which can be used, its specific examples are aluminum,cellulose, polyester, polyethylene and polypropylene and, if necessary,such a film may be layered. Alternatively, its surface may be treatedwith silicon, fluorocarbon or the like or a known additive may becompounded with a liner material so that the detaching property isadjusted or a barrier property is adjusted. In the detachable liner,there may be provided a knob for the detachment so that a handling upondetachment becomes easy.

Further, with an object of adjustment of adhesive property, safety andstability, known additives may be compounded if necessary. Specificexamples thereof are water-absorbing polymers such as Sumikagel SP-520(trade name), Aquakeep 10SH (trade name), Arasorb 800F (trade name) andSanwet 1M-1000MPS (trade name); inorganic fillers such as zinc oxide,calcium carbonate, titanium dioxide and silica substances; solubilizingaids such as glycerol fatty acid ester (e.g., Excel [trade name]) andcrotamiton; other sorbefacients such as aliphatic alcohol (e.g., Kalcohl[trade name]); and moisturizers such as triethyl citrate, polyethyleneglycol and glycerol. They may be appropriately contained in appropriateamounts.

Now a method for the manufacture of the percutaneously absorbingpreparation of the present invention will be illustrated as hereunder.The percutaneously absorbing preparation of the present invention may bemanufactured in such a manner, for example, that all base componentsexcept pharmaceutical ingredient, hexylene glycol and 1-menthol aredissolved by heating, then pharmaceutical ingredient, hexylene glycoland 1-menthol are added thereto and mixed therewith and, after themixture is spread on the above-mentioned support if necessary, it iscovered with a liner followed by cutting into a desired shape to give aproduct or that the mixture is once spread on a film which is subjectedto a detachable treatment and then transferred onto an appropriatesupport with pressure to give a product. It is also possible that allcomponents are dissolved in an organic solvent such as hexane, tolueneor ethyl acetate, the solution is spread on the above-mentioned support,the organic solvent is removed therefrom and the residue is covered by aliner followed by cutting into a desired shape to give a product orthat, after once spreading on a film which is subjected to a detachabletreatment and the organic solvent is removed therefrom followed bytransferring to an appropriate support by compressing to give a product.

EXAMPLES

The percutaneously absorbing patch of the present invention will now beillustrated in more detail by way of Examples and Test Examples ashereunder although the present invention is not limited to thoseexamples. Incidentally, all numerals in Examples, Comparative Examplesand Referential Examples are those % by weight.

EXAMPLE 1

Styrene-isoprene-styrene block copolymer 10 Liquid paraffin 60 Tackifier(alicyclic saturated hydrocarbon 20 resin; trade name: Arkon P-100)Polyisobutylene 7.3 Hexylene glycol 1 1-Menthol 0.1Dibutylhydroxytoluene 1 Estradiol 0.1 Norethisterone 0.5

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone.

EXAMPLE 2

Styrene-isoprene-styrene block copolymer 40 Liquid paraffin 10 Tackifier(rosin ester; trade name: KE-311) 15 Polyisobutylene 2 Hexylene glycol10 1-Menthol 7 Dibutylhydroxytoluene 1 Estradiol 5 Norethisteroneacetate 10

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 3

Styrene-isoprene-styrene block copolymer 19.5 Liquid paraffin 15Tackifier (hydrogenated rosin ester; 60 trade name: Foral 105) Hexyleneglycol 1 1-Menthol 0.5 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 4

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 35.4Tackifier (hydrogenated rosin ester; 30 trade name: Foral 105)Polyisobutylene 8.6 Hexylene glycol 2 1-Menthol 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 5

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 28 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 10Hexylene glycol 7 l-Menthol 1 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 6

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 31 Tackifier(hydrogenated rosin ester; trade name: Foral 105) 30 Polyisobutylene 5Hexylene glycol 7 1-Menthol 3 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 7

Styrene-isoprene-styrene block copolymer 23 Liquid paraffin 31 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 4Hexylene glycol 1 l-Menthol 7 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 8

Styrene-isoprene-styrene block copolymer 23 Liquid paraffin 19.9Tackifier (hydrogenated rosin ester; 40 trade name: Foral 105)Polyisobutylene 3 Hexylene glycol 10 l-Menthol 0.1 Dibutylhydroxytoluene1 Estradiol 1 Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 9

Styrene-isoprene-styrene block copolymer 17 Liquid paraffin 44 Tackifier(hydrogenated rosin ester; 25 trade name: Foral 105) Polyisobutylene 4Hexylene glycol 3 l-Menthol 3 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 10

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 35 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 5Hexylene glycol 2 l-Menthol 4 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 11

Styrene-isoprene-styrene block copolymer 18 Liquid paraffin 30 Tackifier(hydrogenated rosin ester; 34 trade name: Foral 105) Polyisobutylene 4Hexylene glycol 6 l-Menthol 4 Dibutylhydroxytoluene 1 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

EXAMPLE 12

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 26 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 10Hexylene glycol 7 l-Menthol 3 Dibutylhydroxytoluene 1 Ketoprofen 3

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give apreparation of ketoprofen.

EXAMPLE 13

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 26 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 10Hexylene glycol 7 l-Menthol 3 Dibutylhydroxytoluene 1 Oxybutynin 3

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give apreparation of oxybutynin.

EXAMPLE 14

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 26 Tackifier(hydrogenated rosin ester; 30 trade name Foral 105) Polyisobutylene 10Hexylene glycol 7 l-Menthol 3 Dibutylhydroxytoluene 1 Fentanyl citrate 3

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give apreparation of fentanyl citrate.

Comparative Example 1 No Hexyl Glycol Compounded

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 31 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 5l-Menthol 10 Dibutylhydroxytoluene 1 Estradiol 1 Norethisterone acetate2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

Comparative Example 2 No 1 -Menthol Compounded

Styrene-isoprene-styrene block copolymer 20 Liquid paraffin 26 Tackifier(hydrogenated rosin ester; 30 trade name: Foral 105) Polyisobutylene 5Hexylene glycol 15 Dibutylhydroxytoluene 1 Estradiol 1 Norethisteroneacetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

Comparative Example 3 Acrylate Type Base

TS-620 (manufactured by Nippon Carbide) 94 l-Menthol 3 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

Comparative Example 4 Acrylate Type Base

TS-620 (manufactured by Nippon Carbide) 90 Hexylene glycol 7 Estradiol 1Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

Comparative Example 5 Acrylate Type Base

TS-620 (manufactured by Nippon Carbide) 87 Hexylene glycol 7 l-Menthol 3Estradiol 1 Norethisterone acetate 2

The manufacturing method mentioned above was carried out according tothis formulation followed by cutting into a desired size to give a mixedpreparation of estradiol and norethisterone acetate.

Test Example 1 Physical Property of the Preparation

Test pieces of Examples 1, 2, 3, 6, 7, 12, 13 and 14 and those ofComparative Examples 1 and 2 were subjected to an operation that afinger was pushed to the surface of the plaster for about one second forfive times on the same place and cohesive force, finger tack and bleedwere evaluated from the state of the plaster at that time. The result isshown in Table 1.

TABLE 1 Cohesive Force Finger Tack Bleed Example 1 ∘ ∘ ∘∘ Example 2 ∘ ∘∘ Example 3 ∘∘ ∘∘ ∘∘ Example 6 ∘∘ ∘∘ ∘∘ Example 7 ∘ ∘ ∘∘ Example 12 ∘∘∘∘ ∘∘ Example 13 ∘∘ ∘∘ ∘∘ Example 14 ∘∘ ∘∘ ∘∘ Comparative Example 1 x Δ∘ Comparative Example 2 Δ x x

In Table 1, “oo” means “very good”, “o” means “good”, “Δ” means “a bitbad” and “x” means “bad”. In the test pieces of the Examples, there wasno problem in terms of all of cohesive force, tack and bleed while, inthe test piece of Comparative Example 1, there was a problem in cohesiveforce and, in the test piece of Comparative Example 2, the bleed wasnoticed a decrease in finger tack was noted.

Test Example 2 Test on Skin Irritation

The test pieces of Examples 2, 6, 7, 12, 13 and 14 and those ofComparative Examples 1, 3, 4 and 5 were subjected to a skin irritationtest by the following means. Thus, a test piece was applied onto anupper arm of each ten persons (healthy and normal males) and, afterapplication for 24 hours, the skin irritation was evaluated. The resultis shown in Table 2.

TABLE 2 Skin Irritation (SI Value) Example 2 30 Example 6 25 Example 725 Example 12 25 Example 13 25 Example 14 25 Comparative Example 1 40Comparative Example 3 45 Comparative Example 4 45 Comparative Example 545

In Comparative Examples 1, 3, 4 and 5, the result with high skinirritations was noted.

Test Example 3 Test on Skin Permeation

The test pieces of Examples 2, 6, 7 and 11 and Comparative Examples 1, 2and 5 were subjected to a permeation test to the skin of the back(temperature: 37° C.) of hairless mice (6 weeks age; female) using adiffusion cell of a Franz type. After the start of the test, a receptorsolution was collected with predetermined intervals and, immediatelythereafter, a receptor solution was supplemented whereby the amount ofthe pharmaceuticals permeated into the receptor solution was measured bya high performance liquid chromatographic method. Sample numbers foreach test piece were 3. The maximum permeation speeds of estradiol (E₂)and norethisterone acetate (NETA) are shown in Table 3.

TABLE 3 Maximum Permeation Speed (μg/cm²/hr) E₂ NETA Example 2 1.3 1.1Example 6 1.2 1.0 Example 7 1.1 0.9 Example 11 1.2 1.0 ComparativeExample 1 0.5 0.3 Comparative Example 2 0.5 0.4 Comparative Example 50.4 0.3

Preparations of the Examples showed better permeation of thepharmaceuticals than those of the Comparative Examples.

INDUSTRIAL APPLICABILITY

The percutaneously absorbing preparation or, preferably, thepercutaneously absorbing patch of the present invention prepared as suchincreases the permeation of the pharmaceutical ingredient through theskin and shows excellent effects of stable base, good cohesive property,low skin irritation and high skin permeation when hexylene glycol and1-menthol are compounded therewith.

After the percutaneously absorbing patch of the present invention isapplied to the skin of a patient, the pharmaceuticals in atherapeutically effective amount is precisely and surely absorbed fromthe skin.

Moreover, in the percutaneously absorbing preparation of the presentinvention, degree of freedom of the pharmaceutical composition is highand, accordingly, there is a big advantage in a suitable design of highskin permeation of the pharmaceutical ingredient, stability of the baseand efficacy upon therapy.

1. A base for a percutaneously absorbing preparation, comprising 10–40%by weight of styrene-isoprene-styrene block copolymer, 2–10% by weightof polyisobutylene, 10–60% by weight of softener, 20–60% by weight oftackifier, 1–10% by weight of hexylene glycol and 0.1–7% by weight of1-menthol.
 2. A percutaneously absorbing preparation wherein apharmaceutical agent is contained as an effective ingredient in the basefor a percutaneously absorbing preparation according to claim
 1. 3. Thepercutaneously absorbing preparation according to claim 2, wherein thepharmaceutical agent is follicular hormone and/or luteinizing hormone.4. The percutaneously absorbing preparation according to claim 3,wherein the follicular hormone is estradiol, estrone, estriol, equilinor equilenin or a derivative thereof and its compounding amount if is0.1–5% by weight.
 5. The percutaneously absorbing preparation accordingto claim 3, wherein the luteinizing hormone is norethisterone,norethisterone acetate, norethisterone coanthale or progesterone and itscompounding amount is 0.5–10% by weight.